Summary: Endothelial function of the skeletal muscle resistance vasculature declines with advancing age, contributing to maldistribution of muscle blood flow during physical activity and a loss of functional capacity in the elderly. Although aerobic exercise training is commonly prescribed to counter endothelial dysfunction in the elderly, the rate of compliance to aerobic exercise training programs is low, often due to their strenuous nature. Thus, clinically-significant improvements in physical function are not obtained by many individuals placed on aerobic training programs. Thus, there is a need to develop feasible non-pharmacological interventions that enhance blood flow capacity in this population or in high-risk patients who cannot perform moderate aerobic exercise. Low-load, prolonged-duration ankle dorsiflexion, which stretches the muscles of the calf, is prescribed in patients with limited range of motion and to counter foot drop in post-stroke patients. Acute changes in muscle length alter muscle blood flow; therefore, it is likely that repeated, prolonged changes in muscle length, created by dorsiflexion splinting, alter the regulation of muscle blood flow, and represent a viable modality to augment endothelial function and functional capacity in the elderly. Our preliminary results in a rat model of aging indicate that a 3-wk program of daily prolonged-duration, ankle dorsiflexion splinting dramatically improves endothelium-dependent vasodilation of resistance arteries of the soleus muscle. The overarching purpose of the proposed work is to test the hypothesis that performance of daily ankle dorsiflexion splinting improves endothelial function and lower leg muscle blood flow in the elderly. To test this hypothesis we will perform a preclinical study in aged Fischer rats (Aim 1), and clinical study in aged human subjects (Aim 2). In Aim 1, blood flow distribution to the lower hindlimb muscles will be evaluated in vivo during acute splinting and immediately following splint removal. Following 4 wks of daily splinting, hindlimb muscle blood flow will be measured at rest, and during walking exercise. Endothelial function of resistance arteries will be assessed ex vivo, and in vitro analysis of endothelial mechanisms that contribute to enhanced endothelium- dependent dilation will be investigated. In Aim 2, we will test the hypothesis that daily ankle dorsiflexion splinting (4 wks) improves endothelial function of the popliteal artery in sedentary, older human subjects. This work will determine whether a safe, non-invasive intervention (dorsiflexion splinting) can be used to improve leg blood flow in elderly individuals. In addition, a program of daily dorsiflexion splinting, if shown to improve endothelial function and muscle blood flow in healthy older sedentary subjects, could be rapidly translated to clinical populations.